Glycosaminoglycans (GAGs) form an important component of connective tissues, and may be covalently linked to proteins to form proteoglycans, which can act to lubricate interfaces and facilitate relative tissue movement whilst also fulfilling important biological functions. The net negative charge of GAG attracts cations, which in turn attract water molecules. This water is critical to the biomechanical performance of tissues such as the cartilaginous joints and intervertebral discs.
The intervertebral disc is a complex hierarchical structure composed of the annulus fibrosus and nucleus pulposus, which are attached to the vertebral bodies via cartilagenous endplates. The main proteoglycan of the healthy disc is aggrecan, which comprises of a core protein with up to 100 highly sulphated GAG chains (mainly chondroitin and keratan sulphate) covalently attached. The osmotic pressure provided by the sulphated side chains of aggrecan is thought to be responsible for maintaining tissue hydration, which helps to maintain disc height and turgor against high compressive loads. This osmotic pressure is due to the greatly sulphated GAG groups providing a highly fixed negative charge on the matrix. This in turn attracts positively charged molecules such as small cations into the tissue to balance the negative charges. The osmotic response action of the disc is also thought to be important for nutrient and metabolite transport.
Back pain affects a large proportion of the population, with 80% of adults experiencing an episode of back pain during their lifetimes, resulting in a wide range of effects from mild discomfort to complete immobilisation. Back pain is the most common reason given for days off work and it is estimated that the total cost including lost working hours, benefits and healthcare is between 1 and 2% of the gross national product in Western European countries. Lower back pain is strongly associated with degeneration of the intervertebral discs. During degeneration, the aggrecan molecules degrade and the smaller fragments leach from the tissue more readily than the larger portions, which in turn results in a loss of GAGs. The nucleus becomes more fibrotic and less gel-like and there is a loss in disc height, affecting the mechanics of the rest of the spinal column.
Current surgical interventions for low back pain such as spinal fusions and total disc replacements are highly invasive surgical interventions and have relatively poor long term success rates. Therefore, in recent years there has been an interest in developing new therapies to address disc degeneration, such as transplantation, regeneration, repair and replacement. In particular in order to maintain motion in the spinal segment, the replacement of the nucleus without annular obliteration represents a tempting alternative to spinal fusion and total disc replacement procedures.
Considerable effort has been put into tissue engineered approaches to nucleus augmentation. The disc is the largest avascular tissue in the body and therefore has a hostile environment of low pH, low glucose and oxygen levels and high lactate levels. Therefore, a major challenge with tissue engineered approaches is to successfully maintain cell viability. An alternative to cell based therapies is to replace the tissue with a synthetic equivalent.
The aims in any nucleus pulposus replacement are to restore normal load distribution to the diseased level and restore segmental spinal mechanics. In order to be a successful an ideal nucleus replacement device should be: biocompatible without significant systemic or local reactions of toxicity, be stable under varying physiological loading and environmental conditions, be capable of restoring disc height and osmotic pressures and be similar in stiffness to the native tissue. In addition an ideal nucleus replacement device should be implanted using minimally invasive procedures, which limit the destruction of the surrounding tissue, for example, a hydrogel that forms in situ and is injected through a narrow gauge needle as a mobile fluid.
It is known from the prior art (WO 2004/007532) that β-sheet tape forming peptides, which self-assemble in one dimension into a hierarchy of well defined structures, are useful in a variety of biomedical areas. Self-assembling peptides can form long chains and complex structures, which can mimic collagen. These gel forming peptides are advantageous as biomaterials as they are based on entirely natural amino acids, they are highly versatile since they can be made to be either positively or negatively charged, polar or amphiphilic or based on different types of polar uncharged amino acids, and also that the self-assembly can be triggered by external environment such as pH, ionic strength and temperature. Reconstruction of the nucleus pulposus, whilst preserving the biomechanics of the annulus fibrosus and cartilage endplates would offer immediate advantages to patients and clinicians alike.
A nucleus pulposus replacement that can form a stable hydrogel and mimic the mechanical function of natural tissue and that provides a charged environment that will lead to the restoration of the disc swelling pressure would offer immediate advantages to patients and clinicians alike.
A nucleus pulposus replacement that can be injectable and thus minimally invasive would offer immediate advantages to patients and clinicians alike.
An injectable minimally invasive agent that could be used as an early intervention to prevent progression of disc tissue degeneration would offer immediate advantages to patients and clinicians alike.